A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate
Yuki Sakai, … , Go Hirai, Sho Yamasaki
Yuki Sakai, … , Go Hirai, Sho Yamasaki
Published December 24, 2024
Citation Information: J Clin Invest. 2025;135(6):e185443. https://doi.org/10.1172/JCI185443.
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Research Article Immunology Infectious disease

A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate

Abstract

Mycobacterium tuberculosis causes human tuberculosis (TB). As mycobacteria are protected by a thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, the antigenicity of most adjuvantic lipids is unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activated human T cells bearing a unique αβ T cell receptor (αβTCR). This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA-Seq using newly established CD1b-TMM tetramers revealed that TMM-specific T cells were present as CD4+ effector memory T cells in the periphery of uninfected donors but expressed IFN-γ, TNF, and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells were detected in cord blood and PBMCs of donors without bacillus Calmette-Guérin vaccination but were expanded in patients with active TB. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively charged CDR3α, and long CDR3β regions. These results indicate that humans have a commonly shared and preformed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.

Authors

Yuki Sakai, Minori Asa, Mika Hirose, Wakana Kusuhara, Nagatoshi Fujiwara, Hiroto Tamashima, Takahiro Ikazaki, Shiori Oka, Kota Kuraba, Kentaro Tanaka, Takashi Yoshiyama, Masamichi Nagae, Yoshihiko Hoshino, Daisuke Motooka, Ildiko Van Rhijn, Xiuyuan Lu, Eri Ishikawa, D. Branch Moody, Takayuki Kato, Shinsuke Inuki, Go Hirai, Sho Yamasaki

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Figure 5

Ternary complex structure of Y-50 TCR-TMM-CD1b.

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Ternary complex structure of Y-50 TCR-TMM-CD1b. (A) Overall structure of...
(A) Overall structure of the Y-50 TCR-TMM-CD1b complex. The main chains of TCRα, TCRβ, and CD1b are shown. TMM is presented as yellow spheres. (B) Upper panel: Superimposition of the structure of Y-50 TCR alone (PDB: 8XUB) (pink) and Y-50 TCR bound to TMM-CD1b (PDB: 8ZOX) (blue) . Lower panels: CDR3β regions (boxed area in the upper panel) magnified. (C) Close-up view of TMM (R,R) and the side chain of R114 within CDR3α. The β-hydroxy group of TMM is shown in red. (D) Y-50 reporter cells were stimulated with the natural configuration of synthetic TMM (R,R) or non-natural stereoisomers (S,S) or (S,R+R,S) in the presence of CD1b-DC2.4 and analyzed for GFP and CD69 expression. The stereoisomer structures are shown below (R, red; S, black). Data are shown as the mean ± SD of triplicate experiments, and a representative result from 2 independent experiments is shown. (E) Close-up view of TMM (R,R) and the side chain of R107 (CDR3α) and D114 (CDR3β). Hydroxy groups of TMM that formed hydrogen bonds to the TCR side chains are shown in red. (F) Close-up view of the side chains of R79, E80, and D83 in CD1b that interact with the side chains of R37 (CDR1β), Y58 and E63 (CDR2β), and G110 (CDR3β). (G) Multi-bonded interaction of the CD1b RExxD motif and TRBV4-1 residues. Individual interaction is shown by dotted lines. (H) Conservation of the RExxD motif in human CD1b and CD1c. The amino acid sequences of CD1a (NP_001307581), CD1b (NP_001755.1), CD1c (NP_001756.2), and CD1d (NP_001306074) are aligned. Numbers indicate the amino acid position of the mature peptide (excluding signal peptide).